Circulating cytokines in dilated cardiomyopathy and myocarditis and their correlates with biopsy-proven inflammation: a meta-analysis

Background There is increasing interest in circulating cytokines as potential biomarkers in inflammatory myocardial disease. However, their diagnostic utility in reflecting true myocardial inflammation remains uncertain. Purpose To define serum cytokine profiles in heart failure (HF) secondary to dilated cardiomyopathy (DCM) and myocarditis (MCI), and to assess whether circulating cytokines reflect biopsy-proven myocardial inflammation. Methods Systematic review and meta-analysis including 129 studies and 11,606 patients from 27 countries. Standardised mean differences versus healthy controls and ischaemic heart disease (IHD) comparators were calculated. Meta-regression assessed associations with left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), B-type natriuretic peptide (BNP), N-terminal pro–B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP). Sub-analyses incorporated endomyocardial biopsy (EMB)-proven inflammation and myocardial viral positivity. Results Interleukin-6 (IL-6) was robustly elevated in DCM and MCI versus healthy controls without significant publication bias (Egger p=0.31). However, IL-6 levels were comparable to IHD and correlated with HF severity (LVEDD r=0.41; CRP r=0.46) but only weakly with EMB-proven myocardial inflammation (r=0.17). No significant differences in circulating IL-6 levels were observed between EMB-performed and non-EMB DCM cohorts. Tumour necrosis factor-α (TNF-α) elevation in DCM was largely attributable to severe publication bias (Egger p<0.0001); after correction, the effect was non-significant. TNF-α showed minimal association with clinical severity but moderate correlation with EMB inflammation (r=0.42) and viral positivity (r=0.50). Overall, circulating cytokines showed limited discriminatory value for biopsy-proven myocardial inflammation. In MCI, IL-17 and IFN-γ showed the strongest increases. Conclusions Serum IL-6 primarily reflects HF severity and adverse remodelling rather than myocardial inflammatory burden. These findings challenge the role of circulating cytokines as reliable non-invasive markers of myocardial inflammation in DCM, while distinct IL-17- and IFN-γ-driven profiles better characterise MCI.